P1166: BRIGATINIB IN PATIENTS WITH ALK-POSITIVE ANAPLASTIC LARGE CELL LYMPHOMA WHO HAVE FAILED BRENTUXIMAB VEDOTIN
Authors: Layla Veleanu, Bruno Tesson, Laurence Lamant, Ambroise Marçais, Julie Bruneau, Sophie Kaltenbach, Chantal Brouzes, Charlotte Degoutte, Josquin Moraly, Patrick Villarese, Ludovic Lhermitte, Mehdi Latiri, Gregoire Hure, Adrien Chauchet, Caroline Delette, Sylvie Grosleron, Elise Toussaint, Quentin Cabrera, Pauline Brice, Francois-Xavier Gros, Aline Clavert, Lucie Oberic, Marielle Legoff, Sophie Cereja, Fabienne Meggetto, Elizabeth Macintyre, Vahid Asnafi, David Sibon
Journal: HemaSphere (2023)

Topic: 19. Aggressive Non-Hodgkin lymphoma - Clinical Background: ALK-positive anaplastic large cell lymphoma (ALK+ ALCL) patients (pts) who have failed brentuximab vedotin (BV) have a poor prognosis with a median OS after BV failure of 2.9 months and 2‐year OS of 27.1% (Chihara D, 2019). ALK-inhibitors have shown interesting results in relapsed ALK+ ALCL, but in these studies, most pts had not received prior BV, which does not correspond to current standards of treatment in adults. Furthermore, there are currently several ALK-inhibitors, but too few pts available to test them in this rare and difficult-to-treat population. Aims: To evaluate several ALK-inhibitors in preclinical studies, and then to assess the best candidate in a clinical study. Methods: We carried out a preclinical study and then a real-life clinical study. We generated a patient-derived xenograft (PDX) model from a fresh lymph node biopsy of a 41-year-old man newly diagnosed with ALK+ ALCL. Our PDX closely mimicked the patient’s primary tumor, as assessed by pathology, FISH, TCR gene rearrangement, WES and RNA-seq. We used this model to assess 8 ALK-inhibitors (alectinib, brigatinib, ceritinib, crizotinib, ensartinib, entrectinib, lorlatinib, gilteritinib). Results: We selected and recommended brigatinib for clinical off-label use based on our preclinical results and the safety profile in pts with ALK-positive non-small cell lung cancer (NSCLC). Between Jan 2020 and Oct 2022, 15 French adults who have failed BV started brigatinib. At brigatinib initiation, the median age was 35 y (19-73; 2 pts > 60 y), 8/15 were male, the median number of prior treatment lines was 2 (1-8), 4/15 (27%) had received prior crizotinib, including 3 crizotinib-resistant (crizo-R) and 1 crizotinib-sensitive (crizo-S) who relapsed after discontinuation of the drug. 4 pts had previously undergone stem cell transplantation (3 autoSCT, 1 alloSCT). ALCL was refractory to the last treatment in 10/15 pts. 10/11 pts had detectable ALK transcript in blood by RT-PCR. Pts received brigatinib at a dose of 180 mg once daily (with a 7-day lead-in period at 90 mg), as recommended in ALK-positive NSCLC. The best ORR was 93% (14/15) with 73% (11/15) CR according to Lugano response criteria. 2 crizo-R and the crizo-S pts achieved CR, and 1 crizo-R pt reached PR. Time to achieve CR ranged from 8 to 325 days. 9 pts were monitored for ALK transcript in blood over time and kinetics correlated with response. 5 CR pts were bridged to alloSCT. There were 4 progressions/relapses after brigatinib initiation, all occurring within the first 6 months. After a median follow-up of 1.3 years, 1-year PFS and OS were 72% and 85%, respectively. There was no permanent discontinuation of brigatinib related to adverse event (AE), and 3 pts had dose reduction for moderate AE (1 dyspnea and 2 cramps), with complete resolution. Summary/Conclusion: Brigatinib showed high efficacy, including in pts who have failed crizotinib, and was well tolerated. These results should be confirmed in prospective studies.Keywords: Relapsed lymphoma, Kinase inhibitor, ALK/ALCL